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Chapter 9

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Bebhinn Treanor

Chapter 9  Antibodies by themselves are not toxic or destructive to pathogen, only when they bind to them. Several consequences: o Antibodies reduce infection by covering up sites on pathogens surface necessary for growth or replication. Neutralize the pathogen. Neutralizing antibody is used in vaccines o Antibodies also act as molecular adaptors that bind to pathogens with their antigen-binding arms and to receptors on phagocytic cells with their Fc regions. Therefore, opsonization (coating with antibody) of pathogen promotes its phagocytosis o Antibodies bound to surface of pathogens also cause complement fixation through complement activation. This further promotes phagocytosis of pathogen because complement fragments deposited on pathogens surface bind to complement receptors of phagocytes  Antibodies most effective at combating infection are those that are made early in infection and bind strongly to pathogen  B cells need help from activated T cells to mature into antibody secreting plasma cells o This delays onset of antibody production until week after infection  B cells take time to switch isotype and undergo affinity maturation, processes that are needed to produce high affinity antibodies o Therefore, effectiveness of antibodies produced improves steadily  Faster primary response made to certain bacterial antigens that are able to activate B cells without need for T cell help. o Antibodies usually IgM and low affinity o Provide early defense and keep infection at low level  On binding to protein or carbohydrates epitopes on surface of microorganism, surface IgM molecules of naïve, mature B cells become cross linked to each other by antigen and drawn into localized area of contact with microbe o Cluster and aggregation of B cell receptors send signals from receptor complex to inside cell o Associated with cytoplasmic protein tyrosine kinase that is activated by receptor cluster. Activating intracellular signal path (similar to T cell receptor)  Interaction of antigen with surface Ig is communicated to the interior of B cell by proteins Ig and Ig, which are associate with IgM in B cell membrane to form the functional B cell receptor o Cytoplasmic tails of Ig and Ig each contain 2 immunoreceptor tyrosine based activation motifs (ITAMS) with which the tyrosine kinases Blk, Fyn, Lyn associate. (similar to CD3 of T cell receptors) o ITAMS phosphorylate on tyrosine residues allowing tyrosine kinase Syk to bind to Ig tails that are doubly phosphorylated. o Interaction btw bound Syk initiates intracellular signal pathway leading to changes in gene expression in nucleus  Cross linking of B cell receptor by antigen generates signal that’s necessary but not sufficient to activate naïve B cell o Additional signal required are delivered in several ways  Signal delivered when B cell receptor becomes closely associated with another protein complex on B cell surface=B cell co-receptor. B cell co receptor is a complex of 3 proteins.  Complement receptor 2 (CR2 or CD21) that recognizes IC3b and C3d breakdown products of C3b fragments deposited on pathogen  CD19 which acts as signaling chain of the receptor  CD81-function unknown. Cell surface receptor for Hep C  Generation of IC3b and C3d ligands for B cell co-receptor involved the complement receptor CR1, which is also present on B cells o In innate immune response, complement activation by lectin and classical pathways leads to deposition of C3b fragments on pathogens surface o C3b is ligand for the complement CR1 receptor on B cells, which on binding to C3b facilitates its cleavage by factor 1: first to the IC3b fragment and then to the more stable C3d fragment. o By this cooperative process, CR1 increases the B cell co receptors ligands on the pathogen o When B cell receptor binds to its specific antigen on the pathogen, the CR2 component of the B cell coreceptor complex can bind to an adjacent C3d, which serves to bring the B cell receptor and coreceptor into juxtaposition o The co ligation of B cell receptor and co receptor brings the Ig bound tyrosine kinase Lyn into close proximity with cytoplasmic tail of CD19, which it phosphorylates o Phosphorylated CD19 the binds intracellular signaling molecules that generate signals that synergize with those generated by B cell receptor complex o Simultaneous ligation of B cell receptor and coreceptor increases overall signal 1000-10K fold, increasing B cells sensitivity to antigen  For most primary immune response, activation of pathogen specific B cells depends on helper CD4 T cells that recognize pathogen derived peptides presented by the B cells MHC class II molecules o Activating signals emanate from B cell receptor and co receptor and also from cytokine receptors on B cell surface that bind to cytokines produced by helper T cells  Immunodeficient patients who don’t have thymus and T cells have normal number of B cells but cant make antibody responses to most antigens. They can make antibodies against some microbial antigens (thymus independent antigens (TI antigens) o 2 groups: TI-1 antigens and TI-2 antigens, according to type of mechanism by which they activate B cells  TI-1 antigens additional signals provided by the signal receptors of innate immunity like Toll-like receptors o Ex: LPS (lipopolysaccharide) of Gram-negative bacteria is example of TI-1 antigen and is recognized by TLR4 and CD14  Surface associated TI-1 (LPS) causes T cell independent activation of both B cells specific for epitopes of LPS and B cells specific for other non-T1 antigens  Soluble TI-1 that binds to both Toll-like receptor and B-cell receptor only stimulates antibodies against its own epitopes o The aggregate of signals generated when TLR4, B cell receptor and B cell co receptor all recognize their ligands on bacterial cell surface is sufficient to induce the B cells to divide and differentiate o When B cells are triggered by TI-1 antigens they produce only IgM antibodies because cytokines produced by activated helper T cells are necessary for a B cell to switch its antibody isotype  TLR9 (detects bacterial DNA)-most strongly expressed by human B cells o If TLR9 expressing B cell binds to bacterium with B cell receptor and co receptor, it will internalize and degrade bacterium releasing bacterial DNA into endocytic vesicle wheres its detected by TLR9 o B cell activated to make antibodies against the cell surface component of the bacterium recognized by B cell receptor o Because it stimulates TLR9, bacterial DNA acts as TI-9 antigen for the B cells that recognize it with their B cell receptors, stimulating production of anti-DNA antibodies  TI-2 antigens are usually composed of repetitive carbohydrate or protein epitopes present at high density on surface of microorganism o Stimulate only those B cells that are specific for the antigen o Act by cross linking B cell receptors and co receptors so no need for additional signal o B cells responding are often B-1 subpopulation o Antibodies are predominantly IgM (not a lot of isotype switching) o No somatic hypermutation-cant increase affinity for antigen o Although T1-2 antigens something have early antibody response it is limited in scope and duration  Most of the pathogen specific antibody is eventually produced by B cells stimulated by thymus depended antigens o Activation of B cells occur in secondary lymphoid tissues where B cells, specific antigen and helper CD4 T cells brought together  Immature dendritic cells bring pathogens and their antigens from infected tissue to lymph node in the draining lymph o Dendritic cells basically spread the infection from origin to secondary lymphoid tissue…while this happens the dendritic cells mature and go into the T cell area of lymph node o Once in the T cell area, they present antigens to the circulating T cells that enter the node either from blood of afferent lymph o Receptor of antigen specific CD4 T lymphocyte engage complexes of peptide antigens and MHC II on dendritic cell surface=interaction o T cell divides and differentiates into a clone of effector helper T cells o When this differentiation occurs in presence of cytokine IL-4, helper T cells become T H (stays in lymph node) where their job is to activate antigen specific B cells  When B cells enter lymph node, they don’t have to pass an epithelial barrier but are attracted into T cell zones by CCL21 and CCL 19  When Naïve B cells don’t have specific antigens, they are attracted by the chemokine CXCL13 into the B cell zone. o Here, they compete to enter a primary follicle and receive survival signs from follicular dendritic cells before leaving node  If B cell encounters its specific antigen, cross linking of B cell receptor and co receptor induces signals that induce changes in the B cells expression of adhesion molecules and chemokine receptors  These cell surface changes prevent B cells from leaving T cell zone, near the bounding with B cell zone. This location, antigen stimulated B cells are in good place to interact with newly differentiated antigen specific helper CD4 T cells  B cell receptor has 2 distinct roles in B cell activation o Binding antigen, which sends a signal to the B cell’s nucleus to change gene expression o Internalizing antigen by receptor mediated endocytosis, which facilitates its processing and presentation by MHC II  The receptors of the helper T cells sample the MHC II molecules on the antigen-stimulated B cells trapped in the T cell zone, and if they find their specific antigen the T cell and B cell form a conjugate pair o This interaction induces T cell to express CD40 ligand which interacts with B cells CD40 o Signals the B cell to activate transcription factor NFkB and increase surface expression of adhesion molecule ICAM-1, which interacts with integrin LFA-1 on T cell o Strengthens the cognate interaction btw B cell and helper T cell o Immunological synapse is made at the area of contact and T cells cytoskeleton and Golgi Apparatus is reorganized, facilitating the efficient and focused delivery of cytokines onto B cell. o Most important cytokine=IL4, which is involved in T 2 reHponse and essential for B cell prolif and differentiation  Once antigen specific B and T cells form conjugate pair, they move out of the T cell zone in the cortex into the medullary cords. This is where both cells diving forming primary focus of clonal expansion. o Produces dividing B lymphoblasts that secrete IgM o Antibody leaves node and lymph delivers the IgM to blood-goes to infection site o Infections where the pathogen has no thymus independent antigens, this is first antibody produced o Some B lymphoblasts stay in medullary cords to differentiate into plasma cells with the influence of IL5 and IL6 secreted by TH2 cells. They secrete predominantly IgM antibody but some isotype switching occurs in primary focus  Terminal diffe
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